We will study the mechanism through which thyroid hormone controls transcription and mRNA levels for specific genes. Nuclear receptors for thyroid hormone will be purified by column chromatography, by development of antibodies to the receptor by binding to specific DNA sequences. We will attempt to clone the receptor gene by using an expression vector system. A group of cloned thyroid hormone responsive genes will be assembled, and we will determine the DNA sequences, within the genes and flanking elements, to which thyroid hormone receptor binds. These studies will utilize DNA cellulose binding, methylation, and footprinting techniques. We will purify a nuclear protein induced by thyroid hormone treatment, and clone the gene for this protein. The effect of T3 on processing and stabilization of heterogenous nuclear RNA for specific genes will be studied using in vivo and in vitro systems. Receptor function will be studied in cultured fibroblasts from normal subjects and patients with thyroid hormone resistance.